The peroxisome proliferator-activated receptors (PPARs) belong to the steroid receptor superfamily and, as such, are ligand activated transcription factors and exist in different subtypes and isoforms (see, for example, Pershadsingh, H. A., Exp. Opin. Invest. Drugs 8 (1999) 1859-1872; Willson, T. M., et al., J. Med. Chem. 43 (2000) 527-550; Kersten, S., et al., Nature 405 (2000) 421-424; Rami, H. K., and Smith, S. A., Exp. Opin. Ther. Patents 10 (2000) 623-634 and references cited therein). Three subtypes of PPARs (PPAR alpha, PPAR gamma and PPAR delta) have been identified and cloned from mouse and human. PPAR gamma, existing in three isoforms (termed PPAR gamma 1, PPAR gamma 2 and PPAR gamma 3), is the most extensively studied and is considered to be of clinical importance. The antidiabetic activity of different natural and synthetic ligands is correlated with the activation of this receptor.
Thiazolidinediones are a class of compounds that selectively activate PPAR gamma and thus serve as oral insulin-sensitizing agents that lower the blood lipid and blood glucose levels. Exemplary thiazolidinediones are troglitazone, pioglitazone, ciglitazone, rosiglitazone, englitazone, BM 13.1258, BM 15.2054 and derivatives thereof. The PPAR gamma activity of BM 13.1258 and BM 15.2054 has already been reported by Fürnsinn, C., et al. (Br. J. Pharmacol. 128 (1999) 1141-1148) which is incorporated by reference.
Apart from the recognised importance of PPAR gamma agonists in the area of metabolic diseases the discovery of PPAR gamma-dependent modulation of the cell cycle has led to a substantial number of different approaches for the treatment of proliferative diseases utilising compounds that bind to and thereby activate PPAR gamma. In addition to adipose tissue, PPAR gamma is reported to be highly expressed in several cancer cell lines including liposarcoma (lijima, K., et al., Biochem. Biophys. Res. Commun. 247 (1998) 353-356), breast cancer (Mueller, E., et al., Molecular Cell (1998) 465-470; Elstner, E., et al., Proc. Nat. Acad. Sci. USA 95 (1998) 8806-8811), prostate cancer (Kubota, T., et al., Cancer Res. 58 (1998) 3344-3352) and colon cancer (Sarraf, P., et al., Nat. Med. 4 (1998) 1046-1052).
Additionally, troglitazone as a specific PPAR gamma agonist from the thiazolidinedione class is known to inhibit the growth of human cancer cells in vitro and in vivo which is disclosed in some patent applications (WO 98/25598, WO 00/18234, WO 00/30628) and described in a number of papers. In addition, thiazolidinediones including troglitazone have been shown to induce terminal differentiation in human liposarcoma cells (Tontonoz, P., et al., Proc. Nat. Acad. Sci. USA 94 (1997) 237-241). The differentiation of malignant cells represents an ideal concept for treating cancer as opposed to a cell death mediated mechanism.
The PPARs belong to type II steroid receptors that are functionally distinct from the classical steroid receptors and do not bind to their respective binding site to form a homodimer. PPAR gamma heterodimerizes with at least one other member of the steroid receptor family, the retinoid acid receptors, namely RXR alpha (Kliewer, S. A., et al., Nature 358 (1992) 771-774; Tontonoz, P., et al., Mol. Cell. Biol. 15 (1995) 351).
The combination of specific PPAR gamma ligands and RXR alpha ligands activates both receptors, leads to an additive stimulation of differentiation and results in a synergistic inhibition of the cancer cell growth (Tontonoz, P., et al., Proc. Nat. Acad. Sci. USA 94 (1997) 237-241; Elstner, E., et al., Proc. Nat. Acad. Sci. USA 95 (1998) 8806-8811).